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Chapter 2 Epigenetics and Epigenomics 23

overexpression of master transcription factors such as TAL1, LIM TABLE
domain only 1 (LMO1), LMO2, and HOX11 is driven by chromo- 2.1 Emerging Epigenetic Therapies
somal rearrangements involving the T-cell receptor loci.
An alternate mechanism driving TAL1 overexpression in T-ALL Class Target Disease
has recently been described in which small genomic insertions DNA Methylation DNMTs MDS, AML
(2–18 bp) upstream of the TAL1 coding region introduce novel Inhibitors
binding sites for the myeloblastosis (MYB) transcription factor. This
aberrant MYB binding recruits additional transcription factors Runt- Histone-modifying
related transcription factor 1 (RUNX1), GATA3, and TAL1, as well enzymes
as the HAT CREB-binding protein (CBP), and forms a superen- HMT inhibitors DOT1L, EZH2, MLL-rearranged leukemias,
hancer driving leukemogenic TAL1 overexpression. nonspecific NHL, MDS, AML
Many different translocations resulting in fusion of the mixed- HDAC inhibitors HDAC6, nonspecific MM, CLL, lymphoma
lineage leukemia (MLL1/KMT2A) gene, located on chromosome HMT activators SIRT1, SIRT5 MM
11q23, with over 70 different partner proteins have been identified
in infant ALL and therapy-associated acute myeloid leukemia (AML). HDM inhibitors KDM1A AML
The mechanisms underlying the leukemogenic nature of these BET Bromodomain BRD4, nonspecific Hematologic malignancies
translocations have been elucidated only recently. Leukemogenic Inhibitors
MLL1 fusion proteins fuse the N-terminal targeting domain with a AML, Acute myeloid leukemia; BET, bromodomain and extra-terminal motif;
transcription elongation factor such as ENL or AF9. The resulting CLL, chronic lymphocytic leukemia; DNMTs, DNA methyltransferases;
fusion protein drives overexpression of common MLL1 targets by HDAC, histone deacetylase; HDM, histone demethylase; HMT, histone
recruiting the DOT1L complex (having H3K79 methyltransferase methyltransferase; MDS, myelodysplastic syndrome; MLL, mixed-lineage
activity) and the positive transcription elongation factor b (P-TEFb) leukemia; MM, multiple myeloma; NHL, non-Hodgkin lymphoma.
complex (containing CDK9 and phosphorylating RNA polymerase
II). Moreover, a subset of leukemogenic MLL1 fusions can inhibit
the transcriptional repressive activity of PRC1. In summary, MLL
translocations in ALL and AML define a paradigm of leukemia beneficial primarily in treating myelodysplastic syndromes and AML.
development based upon transcriptional dysregulation through aber- The theoretical basis for this therapeutic effect is reactivation of key
rant targeting and control of transcription elongation activity. tumor suppressor genes by disruption of DNA methylation at their
As noted earlier, inactivating mutations in components of chro- promoters. However, this mechanism has not yet been confirmed in
matin remodeling complexes such as SWI/SNF have been identified azacytidine-treated patients, and alternate mechanisms of action are
in a wide variety of human cancers. For example, researchers in a under investigation.
recent study found mutations in the ARID1A subunit of SWI/SNF By far the largest class of epigenetic therapies is inhibitors of
in 17% of patients with Waldenström macroglobulinemia, and histone-modifying enzymes. Drugs inhibiting HMTs and HDACs
patients with ARID1A mutations had more aggressive disease fea- are most prevalent, though several compounds that activate HDACs
tures. In addition to their nucleosome remodeling activities, chroma- or inhibit HDMs are also being developed. For example, inhibitors
tin remodeling complexes contribute to three-dimensional chromatin of the H3K79 methyltransferase DOT1L are in clinical trials for
structure, participate in DNA damage repair, modulate transcription MLL-rearranged leukemias. Alternatively, inhibitors of the H3K27
factor binding, and recruit histone-modifying enzymes. Precisely how methyltransferase EZH2 (the catalytic component of the PRC2
disruption of these many chromatin regulatory activities contributes complex) are being tested in non-Hodgkin lymphoma. Specific
to disease is an extremely active area of research. inhibitors of HDAC6 are being used in trials for multiple myeloma,
In addition to these epigenetic contributions to disease develop- and drugs having broad HDAC inhibitory activity are in ongoing
ment, much interest has evolved in potential epigenetic mechanisms trials for a wide variety of hematologic malignancies.
of resistance to existing cancer therapies. One example of this is The newest class of epigenetic therapies includes the bromodo-
resistance of T-ALL to γ-secretase inhibitors (GSIs), used to target main and extra-terminal motif (BET) bromodomain inhibitors. As
abnormal NOTCH1 activation. Treatment of T-ALL cell lines with discussed briefly earlier, bromodomains are an extremely common
GSIs in vitro kills a large proportion of cells, but it leaves behind feature of DNA-binding proteins and preferentially recognize acety-
a “persister” population of GSI-resistant cells. If GSI treatment is lated chromatin. The abundance of bromodomain-containing DNA-
removed, these persister cells revert to their prior GSI-sensitive state, binding proteins makes development of substrate-specific drugs
suggesting an epigenetic mechanism of drug resistance. A screen of extremely challenging. However, initial clinical trials using BET
chromatin regulators required for persister cell viability identified bromodomain inhibitors having broad binding specificity have been
the bromodomain-containing 4 protein (BRD4), a key factor in very promising in a wide variety of advanced hematologic and non-
activating transcriptional elongation. This study and many others hematologic malignancies. The likely therapeutic targets of these
have ignited broad interest in other potential epigenetic mechanisms drugs are the transcriptional machinery itself, though many additional
of therapy resistance as well as BRD4 as a specific therapeutic mechanisms plausibly contribute.
target.
FUTURE DIRECTIONS
EPIGENETIC THERAPIES
Interpreting the epigenetic code holds great potential for bridging the
Epigenetic therapies are among the most active areas of preclinical gaps between the molecular biology of the genome, cellular biology,
and clinical cancer research because of their potential to specifically and physiology of health and disease. The application of next-
target chromatin-mediated disease mechanisms and the expectation generation sequencing technology and development of novel tech-
that these therapies will have fewer side effects than conventional niques to interrogate chromatin have produced a profusion of new
cytotoxic chemotherapies. As seen in Table 2.1, several classes of epigenetic data. Collaborative epigenomic projects such as ENCODE
drugs have emerged, and the rationales for their ongoing develop- and the Epigenome Roadmap, as well as genomics efforts such as the
ment are briefly discussed next. 1000 Genomes Project and The Cancer Genome Atlas, make these
The first class of epigenetic drugs to show significant clinical vast data widely available to researchers. The substantial challenge
benefit is the DNMT inhibitors, particularly 5-azacytidine and its remains integrating and interpreting these data to generate novel
analogue decitabine. As discussed earlier, abnormal DNA methyla- insights into human health and disease. Substantial collaboration
tion is a common feature of many cancers. However, azacytidine is between biomedical scientists, computational biologists, and